Project Summary Apolipoprotein ?4 (APOE4) allele is the strongest genetic risk factor for Alzheimer's disease (AD). It has been shown that cognitively normal APOE4 carriers develop vascular and metabolic deficits decades before the aggregation of beta-amyloid (A?) and neurofibrillary tau tangles. Emerging evidence shows that the gut microbiota plays a critical role in determining brain metabolic and vascular integrity, and changes in gut microbiome balance have the potential to contribute greatly to AD pathogenesis. The rationale of the study is to determine if dietary interventions can be used to modify gut microbial composition and activity, which will consequently protect brain vascular and metabolic functions, and reduce neuroinflammation and AD-like pathology. We will use a dietary supplement containing prebiotic: Inulin, a non-digestible carbohydrate fiber fermented in the gastrointestinal tract to increase beneficial microbiota, and feed the mice that that overexpresses human A? via 5 familial-AD mutations, and expresses human APOE4 (E4FAD). The central hypothesis is that Inulin is protective of brain functions via the modulation of gut microbiome. We to test the hypothesis by pursuing the following three Specific Aims: 1) Identify Inulin's effects on gut microbiome and associated metabolism using multi-omics; 2) Assess inulin's effects on brain vascular and metabolic functions through neuroimaging; 3) Determine Inulin's effects on neuroinflammation using molecular assays. The project is innovative because it employs novel and multidisciplinary methods to focus on early interventions that may become an effective way to prevent AD-induced dementia for APOE4 carriers via brain-gut axis. The project is also innovative because it challenges the current paradigm as it pertains to AD treatment. Instead of removing A? or tau after they appear or after the onset of cognitive decline, we shift the focus to early interventions that may become an effective way to reduce risk for AD-induced dementia, especially through gut microbiome modulation. The project will have tremendous positive impact as they will enhance our understanding of brain- gut interactions in the context of APOE genotypes. In addition, microbiome analysis and neuroimaging are available for humans, and Inulin-related diets are commercially available; therefore, our approach has high translational value. Outcomes from the study will provide valuable information for future clinical trials with prebiotic diet to reduce AD risk for cognitively normal APOE4 carriers.